The invention refers to a pharmaceutical composition having enhanced antitumor activity and/or reduced side effects.
A significant portion of antitumor agents (cytostatics) destroy tumor cells acting partially via inhibiting the synthesis of DNA and RNA, and partially via damaging the completed DNA. The known antitumour agents may seriously damage genes of healthy cells causing mutations and deletions both in the mitochondrial and the nuclear genoms. Antitumor agents often cause general cell damage besides their primary antitumor effect. This leads to side effects often making continuation of the treatment impossible, and even resulting in the death of patients. Therefore, the most critical part of antitumor treatment is the sensitivity of patient to the serious side effects of cytostatics.
Because of problems cited above, it is of great significance to produce pharmaceutical composition which possesses the antitumour activity of cytostatics or increased antitumor activity thereof without side effects or at least with reduced side effects.
The aim of the invention is to provide a pharmaceutical composition in which the activity of a known antitumor active substance is either enhanced, or said activity is retained and simultaneously the side effects of the known active substance are reduced.
Hydroxiimic acid derivatives of formula (I), 
wherein
R1 is hydrogen or C1-5alkyl group;
R2 represents hydrogen; C1-5alkyl group; C3-8cycloalkyl group; or phenyl group optionally substituted by hydroxyl or phenyl group; or
R1 and R2 together with the adjacent nitrogen atom form a 5 to 8 membered ring optionally containing additional nitrogen, oxygen or sulfur atom(s); and said ring can be condensed with an other alicyclic or heterocyclic ring, preferably with benzene, naphthalene, quinoline isoquinoline, pyridine or pyrazoline ring; furthermore if desired and it possible, nitrogen and/or sulfur as heteroatom(s) are present in the form of an oxide or dioxide;
R3 stands for hydrogen or phenyl, naphthyl or pyridyl group optionally substituted by one or more halogen(s) or C1-4alkoxy group(s);
Y is hydrogen; hydroxyl group; C1-24alkoxy group optionally substituted by amino group; C2-24polyalkenyloxy group containing 1 to 6 double bond(s);
C1-25alkenoyl group; C3-9 alkenoyl group; or a group of formula R7xe2x80x94COOxe2x80x94, wherein R7 is a C2-30polyalkenyl group containing 1 to 6 double bond(s);
X represents halogen; amino group; or C1-4alkoxy group; or
X and B together form an oxygen atom; or
X and Y together with the adjacent carbon atoms and the interjacent xe2x80x94NRxe2x80x94Oxe2x80x94CH2xe2x80x94 group form a ring of formula 
wherein
Z is oxygen or nitrogen;
R is hydrogen; or
R and B together form a chemical bond;
A stands for C1-4alkylene group or a chemical bond; or a group of the formula (b), 
wherein
R4 represents a hydrogen; C1-5alkyl group; C3-8cycloalkyl group; or a phenyl group preferably substituted by halogen C1-4alkoxy or C1-5alkyl group;
R5 stands for a hydrogen; C1-4alkyl group; or a phenyl group;
m is 0, 1 or 2; and
n is 0, 1 or 2
are known from the art.
The U.S. Pat. No. 4,308,399 discloses compounds belonging to the scope of hydroximic acid derivatives of formula (I), which are useful for treatment of the diabetic angiopathy.
The EP-PS No. 417,210 describes hydroximic acid halides, which also fall into the scope of compounds of formula (I), possess a selective B-blocking effect and are useful for treatment of the diabetic angiopathy.
HU-PS published under No. T/66350 discloses a number of other hydroximic acid derivatives being within the scope of compound of formula (I). These known substances are useful in the therapy of vascular deformations, particularly of diabetes mellitus.
It is known from the PCT Patent Application published under No. WO 97/13504 that hydroximic acid derivatives of formula (I) are useful for the prevention and treatment of disorders of mitochondrial origin.
The aim of the present invention is to provide a pharmaceutical composition possessing the effect of the known cytostatic agent but exerting the side effects thereof to a decreased degree.
It has been found that the above aim can be achieved by the pharmaceutical composition to the invention, which comprises a known cytostatic agent or, if desired and possible, a therapeutically useful acid addition salt thereof or therepautically suitable salt thereof and a hydroximic acid derivative of formula (I), wherein E, R1, R2, R3, A, B, X and Y are as defined above, or a therapeutically suitable acid addition salt thereof together with one or more usual carriers.
From the point of invention substituents defined in relation to the formula (I) are as follows: C1-5alkyl represents e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl group, preferably methyl or ethyl group;
C3-8cycloalkyl is e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, preferably cyclopentyl or cyclohexyl group;
the 5 to 8 membered ring may be e.g. pyrrole, pyrazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrmidine, piperazine, morpholine, indole or quinoline ring or the like;
the C1-24alkoxy group may be e.g. methoxy, ethoxy, n-propoxy, tert-butoxy, n-pentoxy, decyloxy, dodecyloxy, octadecyloxy group or the like;
the C1-25alkanoyl group may represent e.g. formyl, acetyl, propionyl, butyryl, caproyl, palmitoyl or stearoyl group and the like;
the C3-9alkenoyl group means e.g. acryloyl, pentenoyl, hexenoyl, heptenoyl, octenoyl group or the like;
the C1-4alkylene group may be e.g. methylene, ethylene, propylene or butylene group;
halogen is e.g. fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Y as R7xe2x80x94COOxe2x80x94 group may be e.g. linolenyol, linoloyl, docosahexanoyl, eicosapentanoyl or arachidonoyl group or the like.
The physiologically (therapeutically) suitable acid addition salts of the compounds of formula (I) are meant to be acid addition salts formed with therapeutically suitable inorganic acids, e.g. hydrochloric or sulfuric acid and the like; or with therapeutically suitable organic acids, e.g. acetic, fumaric or lactic acid and the like.
With the compounds of formula (I), a preferable subgroup consists of hydroximic acid derivatives of formula (II), 
wherein R1, R2, R3, R4, R5, m and n are as defined for formula (I), X means halogen or amino group; and Y stands for hydroxyl group.
Compounds of formula (II) wherein: R1 and R2 together with the adjacent nitrogen atom form a piperidino group; R3 is pyridyl group; both m and n are 0; and X is as defined above, andxe2x80x94particularly preferred. Of these:
O-(3-piperidino-2-hydroxyl-1-propyl)niconitic acid amidoxime dihydrochloride (compound xe2x80x9cLxe2x80x9d) is especially suitable.
Another preferred group of the compounds of formula (I) consists of compounds of formula (III), 
wherein R1, R2, R3 and A are as defined for formula (I).
A third preferred subgroup of hydroximic acid derivatives of formula (I) includes cyclic compounds of formula (IV), 
wherein R1, R2, R3 and A are as defined for formula (I), and Z is oxygen or nitrogen.
A further preferred subgroup of hydroximic acid derivatives of formula (I) comprises compounds of formula (V), 
wherein R1, R2, R3 and A are as defined in formula (I), and R6 stands for C1-4alkyl group
The compounds of formula (I) can be prepared by using processes known from the U.S. Pat. No. 4,308,399, EP-PS No. 417,210, as well as from the published Hungarian Patent Application No. T/66350.
From the viewpoint of activity, a known cytostatic agent (substance) there is such an active agent, which directly or in directly inhibits the DNA synthesis and/or transcription (RNA synthesis) and/or translation of the tumor cell; or injures the developed DNA.
A known pharmaceutical compound with antitumor activity is a compound which directly and/or indirectly inhibits the DNA synthesis and/or transcription (RNA synthesis) and/or translation, and damages the completed DNA in cancerous cell.
In detail, the known pharmaceutical compound with antitumor activity inhibits:
adenosine deaminase,
the biosynthesis of purine base and transformation of the nucleotidess,
biosynthesis of pyrimidine base,
reduction of ribonucleotides,
synthesis of thymidine monophosphate,
synthesis of RNA,
adduct of DNA,
synthesis of DNA,
damage of DNA,
synthesis of purine base and reduction of dihydrofolat,
protein synthesis and deamination of asparagine,
function of proliferation.
From the viewpoint of chemical structure, the known cytostatics may be:
alkylating agents comprising nitrogen-containing mustard derivatives, ethylene imine and methylmelamine derivatives: alkyl sulfonates; nitrosoureas; aziridines; triazenes and the like;
antimetabolites, within these folic acid analogues, pyrimidine analogues, purine analogues and the like;
native substances, including vinca alkaloids, podophyllotoxin, antibiotics and the like;
hormones including adrenocorticosteroids, estrogens, androgens, antiestrogens and the like; and
other substances, such as complex forming agents.
From the known cytostatic active agents, e.g. preferred alkylating agents are as follows:
Preferred antimetabolites are e.g. as follows:
From the known cytostatic active agents, e.g. the following substances of natural origin are favourable:
From the known cytostatic active agents, the hormones described here are advantageous:
From the known cytostatic active agents preferred substances of other classes are e.g.:
The known cytostatic active agent can be used also in the form of its therapeutically suitable acid addition salt, provided that its chemical structure allows the preparation of an acid addition salt. Similarly, the known cytostatic active agent may be used as its therapeutically suitable salt, e.g. metal salt, ammonium salt or salts formed with organic bases, when its chemical structure is suitable for the preparation of such salts.
The cytostatic pharmaceutical composition according to the invention contains preferably cisplatin as cytostatic (antitumor) active agent and 0-(3-piperidino-2-hydroxy-1-propyl)nicotinic acid amidoxime or a therapeutically useful acid addition salt thereof as a hydroximic acid derivative of formula (I).
The pharmaceutical composition according to the invention usually contains the active agents (ingredients) in amounts of 0.1 to 95% by weight, preferably 1 to 50% by weight, preferably 5 to 30% by weight together with the usual carrier(s) of pharmaceutical compositions.
In the pharmaceutical composition according to the invention, the weight ratio of the two active ingredients (agents) is preferably (1 to 50):(50 to 1), particularly preferably (1 to 10):(10 to 1).
The pharmaceutical composition of the invention can be a solid or liquid composition useful for oral, parenteral or rectal administration or topical treatment.
The solid pharmaceutical compositions useful for oral administration can be powders, capsules, tablets, film-coated tablets, microcapsules and the like; and may contain as carrier(s) binders, e.g. gelatine, sorbitol, polyvinylpyrrolidone and the like; filling materials, e.g. lactose, glucose, starch, calcium phosphate and the like; tabletting aids such as magnesium stearate, talc, polyethylene glycol, silicon dioxide ant the like; as well as wetting agents, e.g. sodium lauryl sulfate and the like.
The liquid pharmaceutical compositions for oral administration are solutions, suspensions or emulsions containing as carriers e.g. a suspending agents, such as gelatine, carboxymethylcellulose and the like; emulsifying agents, e.g. sorbitan monooleate; solvents such as water, oils, glycerol, propylene glycol, ethanol; as well as preservatives such as methyl or propyl p-hydroxybenzoate and the like.
The pharmaceutical compositions for parenteral administration are usually the sterile solutions of the active agents.
The dosage forms (dosage units) exemplified above as well as other dosage forms are per se known, sec e.g. the handbook entitled: Remington""s Pharmaceutical Sciences. Edition 18, Mack Publishing Co., Easton, USA (1990).
In most cases, the pharmaceutical, compositions according to the invention contain the dosage unit. For an adult person, the characteristic daily dose is 0.1 to 1000 mg of the known cytostatic active agent and 0.1 to 1000 mg of a compound of formula (I), which can be administered once or in more subdoses. The actual dose depends on several factors and is determined by the physician.